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Project description



Chronic Kidney Disease (CKD) is a leading cause of mortality and morbidity in western countries which is estimated to affect 11% of the adult population. It can progress towards End Stage Renal Disease (ESRD), which has no cure and requires renal replacement therapy i.e., dialysis or renal transplantation.

The number of patients with ESRD is growing consistently with rising cumulative costs that are even greater than the treatment costs of cancer.

In contrast with late stage CKD and ESRD, earlier stages of CKD, when residual function and histology are still preserved, are expected to be treatable with cell therapy.

Because of the complexity of the organ, the development of stem cell therapies for kidney is still in its infancy. The heterogeneous cell populations of renal tissues make cell therapy fundamentally different from most medical treatments.

World leader groups with established expertise in the field of kidney regeneration will cooperate to compare the effects of different stem cell subsets in the same experimental models of acute and chronic renal failure resembling the most important human renal disorders, to establish their efficacy and safety in kidney regeneration.

Three possible sources of stem cells are envisioned to be used: (i) bone-marrow-derived stem cells, (ii) renal adult stem cells, and (iii) fetal renal stem cells. Identifying which cell type is better suitable for beneficial effects, and whether these effects are mediated directly by the transplanted cells or indirectly through involvement of other cell types, would enable the targeted delivery of essential components and is the critical step for the full realization of the potential of this therapeutic approach.

Several studies have already approached the field of kidney regeneration using bone marrow-derived stem cells, adult renal stem cells or fetal renal stem cells in preclinical models of acute and chronic renal failure, with controversial results.

However, the use of different markers to isolate cell preparations, heterogeneous protocols of injection and distinct experimental models of renal failure will help to explain why apparently similar strategies can yield the disparate results described in the literature. A coordinated study of the potential regenerative mechanism in the same experimental models of kidney injuries will allow a greater understanding of the mechanisms influencing transplanted cell survival, which is required to improve efficiency. In addition, a part of this study will be devoted to the assessment of all potential safety concerns, with particular regard to the risk of anomalous differentiation and the long-term possibility of tumorigenicity.

The results of this project will enable standardization of protocols before reaching clinical application.

Although largely auspicated, comparative study involving scientists who independently work in the field of stem cell therapy to set up standardized international protocols for phase I/II trials have not been performed yet, either in the field of kidney regeneration, or for cell therapy of other organs dysfunction. The ultimate success of this study depends on continued and effective coordination of basic and preclinical investigations.

The possibility of bioengineering a a de novo replacement organ using fetal renal stem cells is also explored with an ultimate aim of being able to implant functional renal replacements in patients with end stage renal disease

The most important impact of STAR-T REK is that it will exploit in human clinical trials the knowledge and know how generated by the international leader groups involved in the project, who are joining their resources and efforts for setting up standardized protocols of SC isolation and administration in patients affected by renal failure.

The novelty of this project is that it will assess the regenerative potential of stem cells derived from different sources and investigate the possible obstacles to their utilization (assessment of all potential safety concerns and rigorous toxicology study, with particular regard to the risk of anomalous differentiation and long-term possibility of tumorigenicity) as well as their potential side effects in preclinical models of acute and chronic renal failure.

Description of S&T objectives

Specific objective 1
Isolation of adult bone marrow derived stem and standardization of protocols for autologous cell therapy of renal failure

Specific objective 2
Isolation and characterization of already known types of adult or fetal renal resident stem cells and standardization of protocols for their isolation for cell therapy of renal failure

Specific objective 3
Identification of novel, unknown types of adult or fetal renal stem cells in mouse/rat and human adult kidneys

Specific objective 4
Development and upgrading of techniques of de novo kidney organogenesis

Specific objective 5
Comparison of in vivo renal regenerative potential of stem cells obtained from different sources in animal models of acute and chronic renal failure to set up standardized protocols for clinical trials in humans.

Specific objective 6
Evaluation of the mechanisms at the basis of the renal regenerative potential of stem cells obtained from different sources in animal models of acute and chronic renal failure to set up standardized protocols for clinical trials in humans.

Specific objective 7
Evaluation of safety and immunogenicity of stem cells obtained from different sources in animal models of acute and chronic renal failure to set up standardized protocols for clinical trials in humans.

Specific objective 8
Set up standardized and optimized protocols for phase I/II clinical trials in humans

Thus, all the results will converge in optimized and standardized protocols of stem cell isolation and administration for phase I/II trials in patients affected by acute and chronic renal failure.